The present invention relates to powder analysis and is particularly concerned with a method of analysing powder formed as a mixture of ingredients and derived from a bulk preparation of such a powder.
The present invention was primarily, but not essentially, developed for use in the pharmaceutical industry where it is conventional practice in the commercial production of a product which is, or is to be derived from, a powder for the ingredients of that powder to be loaded into a mixing chamber where they are tumbled or otherwise agitated to ensure thorough mixing of the ingredients. For a pharmaceutical product, the powdered ingredients loaded into the chamber will be one or more active ingredients and one or more excipients. In a typical pharmaceutical facility, the bulk powder mixture will be in the order of 1000 kg and will be intended for sub-division, usually into small containers convenient for retail purposes, into capsules for individual doses of the powder or for processing into individual dose tablets.
Irrespective of the manner in which the bulk powder from the mixing chamber is subsequently processed to be presented for use or retail purposes, in the pharmaceutical industry there are statutory requirements that the ingredients in the form of the pharmaceutical or chemical constituents in end product (typically powder, capsules, or tablets as aforementioned) as presented for retail purposes or use are dispersed uniformly throughout the material of the end product to ensure that dose formulations are identical within prescribed tolerances.
As a consequence, pharmaceutical products derived from powder are subjected to a qualitative and quantitative control analysis, principally to ensure that the end product has required chemical constituents, that the proportions of the required chemical constituents are correct and that the chemical constituents are dispersed uniformly throughout the end product. Where the bulk powder is processed into individual dose tablets, a conventional form of quality control is to subject tablets randomly selected from a production batch to spectrophotometric analysis where a beam of electromagnetic radiation (usually near infraredxe2x80x94NIR) is directed to and transmitted through the selected sample tablet for the transmitted beam to be detected and analysed. From variations in the absorption characteristics exhibited by the ingredients (chemical/pharmaceutical constituents) of the tablet to the applied radiation beam as measured by the detector, it is possible in known manner to effect the required qualitative and quantitative analysis.
Techniques for analysing tablets by NIR spectrophotometric transmission measurements are disclosed in our patent specification EP-A-0,896,215 and in EP-A-0767369.
Once production has started to sub-divide a bulk powder mixture into discrete weights or doses and to package those doses typically into capsules or to press them into tablets, production rates are so fast that if analysis of the final product indicates that the ingredients, particularly active ingredients, are not uniformly dispersed throughout the bulk powder mixture, there is likely to be considerable wastage and expense (both in materials and in production), in the products which were made prior to a decision to stop production.
As a consequence (and in some countries it is a statutory requirement in the production of pharmaceutical products from powder mixtures), it is conventional practice to analyse samples of powder derived from the bulk mixture in the mixing chamber to ensure appropriate homogenity and concentration of the active and excipient ingredients within the bulk mixture before its sub-division commences. For this analysis several powder samples are taken from the bulk mixture at locations spaced from each other and at various depths in the mixture to give an overall picture of how well the ingredients are homogenised throughout the blend or mix.
Each powder sample that is removed from the bulk powder mixture is assessed for homogenity of its ingredients and conventionally this is achieved by either of two well-known techniques. The longest standing and probably most utilised technique is that of high performance liquid chromatography (HPLC) which is well-known in the art and as such need not be discussed in detail. However despite its popularity, it is recognised that HPLC has distinct disadvantages notably a) it utilises toxic solvents and therefore it has to be used in a facility remote from the chemical/pharmaceutical manufacturing facility for good manufacturing practice, b) the analysis can take many hours or days by experienced personnel with consequent expense and delays in production time, and c) it is suitable only for determining concentration throughout the mixture of the or a particular active ingredient in the mixture.
The second technique is spectrophotometric analysis of the powder sample by reflectance measurements of a near infrared (NIR) beam. For each sample, a tablet dose weight is weighed into a glass vial or other container and the sample is then scanned. The sample is then mixed and scanned againxe2x80x94this procedure is repeated five times and the resultant spectra are then averaged. Spectrophotometric analysis of powder by reflectance measurements is discussed in connection with our patent publication WO 95/00831. The tablet dose weight is used for the analysis (although up to three times such a dose weight is permitted for the analysis) in accordance with regulations laid down by recognised pharmaceutical bodies on the basis that if a much larger weight from the sample is used, it could suggest that a mixture is properly homogenised when in fact it is not. The sample is scanned five times due the nature of the depth of penetration of the NIR light beam. Tests have shown that using standard NIR reflectance optics, the NIR beam will only pass into a fine white powder up to a depth of 0.5 mm. As a consequence, to get a representative view and useable cross section of the whole sample, the powder has to be mixed and scanned five times and the resultant spectra averaged. Homogenity of the mixture is then usually determined by calculating the standard deviation of the samples at absorption characteristics which are unique to the active ingredient or ingredients. The numerous scanning and re-mixing of powder from each sample is a lengthy procedure which causes consequential delays in production and is preferably carried out by experienced laboratory personnel. Overall therefore this second technique of analysis is generally regarded as expensive and of suspect accuracy due to the inability of the NIR beam to scan efficiently a relatively thick surface layer of powder.
From the foregoing, it will be realised that there is a need to provide a method of analysing powder formed from a mixture of ingredients and prepared in bulk (particularly but not essentially for pharmaceutical and/or chemical products) and which method alleviates the disadvantages of the above described prior proposals. It is an object of the present invention to satisfy this need. More particularly, the present invention has as its aims to provide a method of analysing powder formed as a mixture of ingredients and derived from a bulk preparation which permits a fast analysis that may be used efficiently by inexperienced personnel to alleviate personnel error and delays in production and to provide an accurate analysis on the basis of which an assessment can be made on the acceptability or otherwise of the homogenity and concentration of either or both active ingredients and excipients in the bulk powder mixture or blend.
According to the present invention, there is provided a method of analysing powder formed as a mixture of ingredients and derived from a bulk preparation thereof which comprises predetermining an assay standard spectrum for a relevant ingredient of the bulk powder mixture by spectrophotometrically analysing characteristics of that relevant ingredient from transmission measurements of a beam of electromagnetic radiation applied to and passing through the relevant ingredient to provide a spectrum of absorption characteristics at known wavelengths of the beam; removing a sample of powder from the bulk mixture and pressing powder of the sample into a self-supporting test wafer; spectrophotometrically analysing characteristics of the material of the test wafer from transmission measurements of the beam of electromagnetic radiation applied to and passing through the wafer to provide an assay test spectrum of actual absorption characteristics of ingredients in the material of the test wafer for known wavelengths of the beam, and comparing absorption characteristics from said assay standard spectrum with said assay test spectrum at predetermined wavelengths of the beam to assess acceptability of the relevant ingredient in the powder of the sample.
By the present invention, sample powder removed from the bulk mixture of powder ingredients as prepared for subsequent processing is subjected to spectrophotometric analysis by a beam of electromagnetic radiation (usually and hereinafter referred to as near infraredxe2x80x94NIR) that is transmitted through the material of the powder sample following that material being compressed into a self-supporting wafer.
The self-supporting characteristics of the wafer are intended so that the wafer may be handled relatively freely for fitting into the spectrometer without disintegrating and to avoid the possible interference of glass supports in the spectrum obtained. Typically the wafer will be formed with powder from an extracted sample amounting to approximately 0.5 to 1.5 (preferably 1.0) dose weight of tablets or capsules which may be intended to be produced from the bulk powder material. This powder dose weight may quickly and easily be compressed into a wafer utilising a simple barrel and cylinder moulding press so that the wafer may be formed by unskilled operatives. Similarly such an unskilled operative may locate the wafer in a wafer holder of a spectrometer and actuate the spectrophotometric system to provide the required assay test spectra.
Relevant ingredients, be they either active or excipient, in the bulk powder mixture will be known and each relevant ingredient is subjected to spectrophotometric analysis to provide an assay standard spectrum. This assay standard spectrum is preferably achieved by use of a self-supporting standard wafer of the respective relevant ingredient similarly sized to the test wafer formed from the bulk powder sample. By comparing the assay test spectrum of the actual absorption characteristics of ingredients in the material of the test wafer formed from the sample of the bulk powder material with the assay standard spectra of the relevant ingredients it is possible to assess the quantitative presence of the relevant ingredients in the powder sample. This latter assessment may also be made by unskilled personnel quickly and efficiently.
It is also possible to provide the required assay standard spectrum from a sample of powder which includes the relevant ingredient and which sample has already been determined as being accurate in the quantity and distribution of the relevant ingredient, for example, by HPLC. This validation of the accuracy of the spectroscopy by comparison with chromotographical testing is likely to require skilled personnel, but having once determined the assay standard spectrum that data is available for use by unskilled personnel in carrying out the method of the present invention.
In practice, it will be usual for an operative to remove two or more samples of powder from spaced locations (both horizontally and vertically) in the bulk mixture and to press similar self-supporting wafers from the samples and to provide assay test spectra for the respective wafers. Absorption characteristics from the assay standards are then compared with the respective assay test spectra at appropriate wavelengths of the beam to assess acceptability of the distribution and the concentration of the relevant ingredients throughout the bulk mixture. It will be appropriate for experienced or skilled personnel to determine permissible tolerances in the distribution of the relevant ingredients but once these have been set, it is possible for an unskilled operator to quickly determine whether the homogenity of the distribution of respective ingredients throughout the bulk powder mixture is acceptable for that mixture to proceed to further processing such as tableting or encapsulation of individual dose weights.
The method of the present invention will permit analysis of the bulk powder mixture to be effected by unskilled personnel quickly and efficiently in the vicinity of a production facility for good manufacturing practice thereby alleviating considerable expense which may otherwise be incurred from lengthy delays in production frequently caused by use of conventional analysis techniques.
A preferred feature of the present invention is that the powder of the sample is pressed into a wafer having flat, parallel and opposed end faces and that the NIR beam is directed perpendicularly through those flat end faces. Such a flat faced wafer is advantageous in that it provides efficient transmission characteristics for the NIR beam to be effective over a wide band wavelength in the spectrum of the transmitted beam. In comparison, conventional tablets tend to have convexly curved opposed end faces on which may be embossed or engraved trade marks or other indicia and when such tablets are subjected to spectrophotometric analysis by transmission it is found that the resultant spectrum from the transmitted beam is useable over a relatively narrow wavelength band due to light scatter and stray light resulting from the convex and possibly undulating profile presented by the opposed end faces of the tablet.
Furthermore, by use of a flat faced wafer, it is convenient and efficient to mount the wafer in a holder of the spectrometer with flat faces in face to face contact to alleviate stray light from the applied or incident NIR beam from being directed into the detector between the wafer and the wafer holder (rather than by passing through the material of the wafer).
A further advantage of the present invention is that in a production facility where the bulk powder mixture is to be processed into tablets, the spectrometer and detector as used for the analysis of the material in the wafer derived from the powder sample can also be used for spectrophotometric analysis of tablets produced from the powder mixture in accordance with the disclosure in our patent specification EP-A-0,896,215.